rs35554503

chr14-63977907-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182914.3(SYNE2):c.1296C>A(p.Ser432Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,607,958 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (93 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (93 hom.)
• Consequence: SYNE2 NM_182914.3 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.706

Genes affected

SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018267334).
• BP6: Variant 14-63977907-C-A is Benign according to our data. Variant chr14-63977907-C-A is described in ClinVar as [Benign]. Clinvar id is 130469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.1296C>A	p.Ser432Arg	missense_variant, splice_region_variant	13/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.1296C>A	p.Ser432Arg	missense_variant, splice_region_variant	13/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2811 AN: 152012 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0645

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00464 AC: 1156 AN: 249250 Hom.: 39 AF XY: 0.00355 AC XY: 480 AN XY: 135230

Gnomad AFR exome AF: 0.0660

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00191 AC: 2775 AN: 1455828 Hom.: 93 Cov.: 29 AF XY: 0.00164 AC XY: 1189 AN XY: 724654

Gnomad4 AFR exome AF: 0.0655

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000949

Gnomad4 OTH exome AF: 0.00462

GnomAD4 genome AF: 0.0186 AC: 2823 AN: 152130 Hom.: 93 Cov.: 32 AF XY: 0.0177 AC XY: 1319 AN XY: 74368

Gnomad4 AFR AF: 0.0646

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00464 Hom.: 19

Bravo AF: 0.0219

ESP6500AA AF: 0.0600 AC: 223

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00573 AC: 692

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	17
Dann	Benign	0.90
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.68	T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;L;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N;.;N;N
REVEL	Benign	0.12
Sift	Benign	0.051	T;.;T;T
Sift4G	Uncertain	0.050	T;D;T;D
Polyphen		0.012	B;.;B;.
Vest4		0.29
MutPred		0.13		Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);
MVP		0.36
MPC		0.052
ClinPred		0.0076	T
GERP RS		4.7
Varity_R		0.10
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35554503; hg19: chr14-64444625;